Synthesis and in vitro anticancer evaluation of some fused indazoles, quinazolines and quinolines as potential EGFR inhibitors

Abstract

derivatives of benzo[g]indazole 5a, b, benzo[h]quinazoline 7, 12a-c, 13a-c and 15a-c and benzo[h]quinoline 17a-c and 19a-c were synthesized from 6-methoxy-3,4-dihydronaphthalen-1(2H)-one (1). Anticancer activity of all the synthesized compounds was evaluated against four cancerous cell lines; HepG2, MCF-7, HCT116 and Caco-2. MCF-7 cells emerged as the most sensitive cell line against the target compounds. All the examined compounds, except 5a and 5b, displayed potent to moderate anticancer activity against MCF-7 cells with an IC₅₀ values ranging from 7.21 to 21.55 µM. In particular, compounds 15c and 19b emerged as the most potent derivatives against EGFR-expressing MCF-7 cells with IC₅₀ values = 7.70 ± 0.39 and 7.21 ± 0.43 μM, respectively. Additionally, both compounds did not display any significant cytotoxicity towards normal BHK-21 fibroblast cells (IC₅₀ value > 200 µM), thereby providing a good safety profile as anticancer agents. Furthermore, compounds 15c and 19b displayed potent inhibitory activity towards EGFR in the sub-micromolar range (IC₅₀ = 0.13 ± 0.01 and 0.14 ± 0.01 μM, respectively), compared to that of Erlotinib (IC₅₀ = 0.11 ± 0.01 μM). Docking studies for 15c and 19b into EGFR active site was carried out to explore their potential binding modes. Therefore, compounds 15c and 19b can be considered as interesting candidates for further development of more potent anticancer agents.

Keywords: Anticancer; Benzo[g]indazole; Benzo[h]quinazoline; Benzo[h]quinoline; EGFR inhibitors; Molecular docking.